Vinblastine

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Vinblastine
Vinblastine2DCSD.svg
Vinblastine ball-and-stick.png
Clinical data
Trade names Velban, Velbe, others
Other namesvincaleukoblastine
AHFS/Drugs.com Monograph
MedlinePlus a682848
License data
Pregnancy
category
  • AU:D
Routes of
administration 		intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability n/a
Metabolism Liver (CYP3A4-mediated)
Elimination half-life 24.8 hours (terminal)
Excretion Bile duct and kidney
Identifiers
  • dimethyl (2β,3β,4β,5α,12β,19α)-15-[(5S,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-1,4,5,6,7,8,9,10-octahydro-2H-3,7-methanoazacycloundecino[5,4-b]indol- 9-yl]-3-hydroxy-16-methoxy-1-methyl-6,7-didehydroaspidospermidine-3,4-dicarboxylate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.011.577 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C46H58N4O9
Molar mass 810.989 g·mol−1
3D model (JSmol)
  • [H][C@]89CN(CCc1c([nH]c2ccccc12)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@@]5([H])[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]7(CC)C=CCN6CC[C@]45[C@@]67[H])C8)C[C@](O)(CC)C9
  • InChI=1S/C46H58N4O9/c1-8-42(54)23-28-24-45(40(52)57-6,36-30(15-19-49(25-28)26-42)29-13-10-11-14-33(29)47-36)32-21-31-34(22-35(32)56-5)48(4)38-44(31)17-20-50-18-12-16-43(9-2,37(44)50)39(59-27(3)51)46(38,55)41(53)58-7/h10-14,16,21-22,28,37-39,47,54-55H,8-9,15,17-20,23-26H2,1-7H3/t28-,37+,38-,39-,42+,43-,44-,45+,46+/m1/s1 Yes check.svgY
  • Key:JXLYSJRDGCGARV-XQKSVPLYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Vinblastine (VBL), sold under the brand name Velban among others, is a chemotherapy medication, typically used with other medications, to treat a number of types of cancer. [1] This includes Hodgkin's lymphoma, non-small-cell lung cancer, bladder cancer, brain cancer, melanoma, and testicular cancer. [1] It is given by injection into a vein. [1]

Contents

Most people experience some side effects. [1] Commonly it causes a change in sensation, constipation, weakness, loss of appetite, and headaches. [1] Severe side effects include low blood cell counts and shortness of breath. [1] It should not be given to people who have a current bacterial infection. [1] Use during pregnancy will likely harm the baby. [1] Vinblastine works by blocking cell division. [1]

Vinblastine was isolated in 1958. [2] An example of a natural herbal remedy that has since been developed into a conventional medicine, vinblastine was originally obtained from the Madagascar periwinkle. [3] It is on the World Health Organization's List of Essential Medicines. [4]

Medical uses

Vinblastine is a component of a number of chemotherapy regimens, including ABVD for Hodgkin lymphoma, and along with methotrexate in the treatment of aggressive fibromatosis (desmoid tumor). [5] [6] It is also used to treat histiocytosis according to the established protocols of the Histiocytosis Association.

Side effects

Adverse effects of vinblastine include hair loss, loss of white blood cells and blood platelets, gastrointestinal problems, high blood pressure, excessive sweating, depression, muscle cramps, vertigo and headaches. [7] [1] As a vesicant, vinblastine can cause extensive tissue damage and blistering if it escapes from the vein from improper administration. [8]

Pharmacology

Vinblastine is a vinca alkaloid [9] [2] [10] and a chemical analogue of vincristine. [11] [12] It binds tubulin, thereby inhibiting the assembly of microtubules. [13] Vinblastine treatment causes M phase specific cell cycle arrest by disrupting microtubule assembly and proper formation of the mitotic spindle and the kinetochore, each of which are necessary for the separation of chromosomes during anaphase of mitosis. Toxicities include bone marrow suppression (which is dose-limiting), gastrointestinal toxicity, potent vesicant (blister-forming) activity, and extravasation injury (forms deep ulcers). Vinblastine paracrystals may be composed of tightly packed unpolymerized tubulin or microtubules. [14]

Vinblastine is reported to be an effective component of certain chemotherapy regimens, particularly when used with bleomycin and methotrexate in VBM chemotherapy for Stage IA or IIA Hodgkin lymphomas. The inclusion of vinblastine allows for lower doses of bleomycin and reduced overall toxicity with larger resting periods between chemotherapy cycles. [15]

Mechanism of action

The complex of tubulin and vinblastine. Vinblastine is shown in yellow. Tublin&vinblastin-1Z2B.png
The complex of tubulin and vinblastine. Vinblastine is shown in yellow.

Microtubule-disruptive drugs like vinblastine, colcemid, and nocodazole have been reported to act by two mechanisms. [16] At very low concentrations they suppress microtubule dynamics and at higher concentrations they reduce microtubule polymer mass. Recent findings indicate that they also produce microtubule fragments by stimulating microtubule minus-end detachment from their organizing centers. Dose-response studies further indicate that enhanced microtubule detachment from spindle poles correlate best with cytotoxicity. [17] But research into the mechanism is still ongoing as recent studies also show vinblastine inducing apoptosis that is phase-independent in certain leukemias. [18]

Pharmacokinetics

Vinblastine appears to be a peripherally selective drug due to limited brain uptake caused by binding to P-glycoprotein. [19] [20]

Isolation and synthesis

Vinblastine may be isolated from the Madagascar Periwinkle ( Catharanthus roseus ), its only known biological producer, [21] along with several of its precursors, catharanthine and vindoline. Extraction is costly and yields of vinblastine and its precursors are low, although procedures for rapid isolation with improved yields avoiding auto-oxidation have been developed. Enantioselective synthesis has been of considerable interest in recent years, as the natural mixture of isomers is not an economical source for the required C16'S, C14'R stereochemistry of biologically active vinblastine. Initially, the approach depends upon an enantioselective Sharpless epoxidation, which sets the stereochemistry at C20. The desired configuration around C16 and C14 can then be fixed during the ensuing steps. In this pathway, vinblastine is constructed by a series of cyclization and coupling reactions which create the required stereochemistry. The overall yield may be as great as 22%, which makes this synthetic approach more attractive than extraction from natural sources, whose overall yield is about 10%. [22] Stereochemistry is controlled through a mixture of chiral agents (Sharpless catalysts), and reaction conditions (temperature, and selected enantiopure starting materials). [23] Due to difficulty of stereochemical restraints in total synthetic processes, other semi-synthetic methods from precursors, catharanthine and vindoline, continue to be developed. [24]

History

Vinblastine was first isolated by Robert Noble and Charles Thomas Beer at the University of Western Ontario from the Madagascar periwinkle plant. Vinblastine's utility as a chemotherapeutic agent was first suggested by its effect on the body when an extract of the plant was injected in rabbits to study the plant's supposed anti-diabetic effect. (A tea made from the plant was a folk-remedy for diabetes.) The rabbits died from a bacterial infection, due to a decreased number of white blood cells, so it was hypothesized that vinblastine might be effective against cancers of the white blood cells such as lymphoma. [25] It was approved by FDA in 1965. [13]

Related Research Articles

<span class="mw-page-title-main">Chemotherapy</span> Treatment of cancer using drugs that inhibit cell division or kill cells

Chemotherapy is the type of cancer treatment that uses one or more anti-cancer drugs in a standard regimen. Chemotherapy may be given with a curative intent, or it may aim only to prolong life or to reduce symptoms. Chemotherapy is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer, which is called medical oncology.

<i>Catharanthus</i> Genus of flowering plants

Catharanthus is a genus of flowering plants in the family Apocynaceae. Like the genus Vinca, they are known commonly as periwinkles. There are eight known species. Seven are endemic to Madagascar, though one, C. roseus, is widely naturalized around the world. The eighth species, C. pusillus, is native to India and Sri Lanka. The name Catharanthus comes from the Greek for "pure flower".

<span class="mw-page-title-main">Tubulin</span> Superfamily of proteins that make up microtubules

Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoskeleton. It was discovered and named by Hideo Mōri in 1968. Microtubules function in many essential cellular processes, including mitosis. Tubulin-binding drugs kill cancerous cells by inhibiting microtubule dynamics, which are required for DNA segregation and therefore cell division.

<span class="mw-page-title-main">Vincristine</span> Chemical compound; chemotherapy medication

Vincristine, also known as leurocristine and marketed under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's disease, neuroblastoma, and small cell lung cancer among others. It is given intravenously.

<i>Vinca</i> Genus of flowering plants

Vinca is a genus of flowering plants in the family Apocynaceae, native to Europe, northwest Africa and southwest Asia. The English name periwinkle is shared with the related genus Catharanthus.

<span class="mw-page-title-main">History of cancer chemotherapy</span>

The era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs. The targeted therapy revolution has arrived, but many of the principles and limitations of chemotherapy discovered by the early researchers still apply.

<span class="mw-page-title-main">Vinorelbine</span> Pharmaceutical drug

Vinorelbine (NVB), sold under the brand name Navelbine among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer and non-small cell lung cancer. It is given by injection into a vein or by mouth.

<span class="mw-page-title-main">Dacarbazine</span> Chemotherapy medication

Dacarbazine, also known as imidazole carboxamide and sold under the brand name DTIC-Dome, is a chemotherapy medication used in the treatment of melanoma and Hodgkin's lymphoma. For Hodgkin's lymphoma it is often used together with vinblastine, bleomycin, and doxorubicin. It is given by injection into a vein.

Stanford V, is a chemotherapy regimen intended as a first-line treatment for Hodgkin lymphoma. The regimen was developed in 1988, with the objective of maintaining a high remission rate while reducing the incidence of acute and long term toxicity, pulmonary damage, and sterility observed in alternative treatment regimens such as ABVD. The chemical agents used are:

<i>Catharanthus roseus</i> Species of flowering plant in the family Apocynaceae

Catharanthus roseus, commonly known as bright eyes, Cape periwinkle, graveyard plant, Madagascar periwinkle, old maid, pink periwinkle, rose periwinkle, is a perennial species of flowering plant in the family Apocynaceae. It is native and endemic to Madagascar, but is grown elsewhere as an ornamental and medicinal plant, and now has a pantropical distribution. It is a source of the drugs vincristine and vinblastine, used to treat cancer. It was formerly included in the genus Vinca as Vinca rosea.

<i>Vinca</i> alkaloid

Vinca alkaloids are a set of anti-mitotic and anti-microtubule alkaloid agents originally derived from the periwinkle plant Catharanthus roseus and other vinca plants. They block beta-tubulin polymerization in a dividing cell.

ABVD is a chemotherapy regimen used in the first-line treatment of Hodgkin lymphoma, replacing the older MOPP protocol. It consists of concurrent treatment with the chemotherapy drugs:

<span class="mw-page-title-main">Vindesine</span> Chemical compound

Vindesine, also termed Eldisine, is a semisynthetic vinca alkaloid derived from the flowering plant Catharanthus roseus. Like the natural and semisynthetic vinca alkaloids derived from this plant, vindesine is an inhibitor of mitosis that is used as a chemotherapy drug. By inhibiting mitosis, vinedsine blocks the proliferation of cells, particularly the rapidly proliferation cells of certain types of cancer. It is used, generally in combination with other chemotherapeutic drugs, in the treatment of various malignancies such as leukaemia, lymphoma, melanoma, breast cancer, and lung cancer.

<span class="mw-page-title-main">Mitotic inhibitor</span> Cell division inhibitor

A mitotic inhibitor, microtubule inhibitor, or tubulin inhibitor, is a drug that inhibits mitosis, or cell division, and is used in treating cancer, gout, and nail fungus. These drugs disrupt microtubules, which are structures that pull the chromosomes apart when a cell divides. Mitotic inhibitors are used in cancer treatment, because cancer cells are able to grow through continuous division that eventually spread through the body (metastasize). Thus, cancer cells are more sensitive to inhibition of mitosis than normal cells. Mitotic inhibitors are also used in cytogenetics, where they stop cell division at a stage where chromosomes can be easily examined.

Brentuximab vedotin, sold under the brand name Adcetris, is an antibody-drug conjugate medication used to treat relapsed or refractory Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), a type of T cell non-Hodgkin lymphoma. It selectively targets tumor cells expressing the CD30 antigen, a defining marker of Hodgkin lymphoma and ALCL. The drug is being jointly marketed by Millennium Pharmaceuticals outside the US and by Seagen in the US.

<span class="mw-page-title-main">Monomethyl auristatin E</span> Chemical compound

Monomethyl auristatin E (MMAE) is a synthetic antineoplastic agent. Because of its toxicity, it cannot be used as a drug itself; instead, it is linked to a monoclonal antibody (MAB) which directs it to the cancer cells. In International Nonproprietary Names for MMAE-MAB-conjugates, the name vedotin refers to MMAE plus its linking structure to the antibody. It is a potent antimitotic drug derived from peptides occurring in marine shell-less mollusc Dolabella auricularia called dolastatins which show potent activity in preclinical studies, both in vitro and in vivo, against a range of lymphomas, leukemia and solid tumors. These drugs show potency of up to 200 times that of vinblastine, another antimitotic drug used for Hodgkin lymphoma as well as other types of cancer.

<span class="mw-page-title-main">Plant sources of anti-cancer agents</span>

Plant sources of anti-cancer agents are plants, the derivatives of which have been shown to be usable for the treatment or prevention of cancer in humans.

VAMP regimen or VAMP chemotherapy is a four-drug combination chemotherapy regimen, used today in the treatment of Hodgkin lymphoma. It was one of the earliest combination chemotherapy regimens, originally developed as a treatment for childhood leukemia by a group of researchers at the National Cancer Institute led by Emil Frei and Emil Freireich. The first clinical trial of VAMP began in 1961. Because it was the first time that four chemotherapeutic agents were used at once, the trial was highly controversial at its time. Although new combination chemotherapy regimens have replaced the use of VAMP in the treatment of childhood leukemia, VAMP is considered an important precursor to modern treatments, confirming the effectiveness of combination chemotherapy and leading to the use of combination chemotherapy regimens to treat other types of cancer.

This is a historical timeline of the development and progress of cancer treatments, which includes time of discovery, progress, and approval of the treatments.

<span class="mw-page-title-main">Dimerization of catharanthine and vindoline</span>

Catharanthine and vindoline are terpenoid indole alkaloids naturally produced within the Madagascar periwinkle plant whose dimerization produces the anti-cancer drugs vinblastine and vincristine. The precursor of catharanthine and vindoline is strictosidine, the common precursor of all indole alkaloids. The localization of catharanthine and vindoline within the plant tissue has been heavily studied in recent years with conflicting results. The dimerization of catharanthine and vindoline to form vinblastine and vincristine is catalyzed by a peroxidase and a reductase, and includes several intermediate compounds.

References

  1. 1 2 3 4 5 6 7 8 9 10 "Vinblastine Sulfate". The American Society of Health-System Pharmacists. Archived from the original on 2 January 2015. Retrieved 2 January 2015.
  2. 1 2 Ravina E (2011). The evolution of drug discovery : from traditional medicines to modern drugs (1. Aufl. ed.). Weinheim: Wiley-VCH. p. 157. ISBN   9783527326693. Archived from the original on 1 August 2017.
  3. ↑ Liljefors T, Krogsgaard-Larsen P, Madsen U (2002). Textbook of Drug Design and Discovery (Third ed.). CRC Press. p. 550. ISBN   9780415282888. Archived from the original on 20 December 2016.
  4. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  5. ↑ Rueda Domínguez A, Márquez A, Gumá J, Llanos M, Herrero J, de Las Nieves MA, et al. (December 2004). "Treatment of stage I and II Hodgkin's lymphoma with ABVD chemotherapy: results after 7 years of a prospective study". Annals of Oncology. 15 (12): 1798–1804. doi: 10.1093/annonc/mdh465 . PMID   15550585.
  6. ↑ Lee YS, Joo MW, Shin SH, Hong S, Chung YG (January 2024). "Current Treatment Concepts for Extra-Abdominal Desmoid-Type Fibromatosis: A Narrative Review". Cancers. 16 (2): 273. doi: 10.3390/cancers16020273 . PMC   10813957 . PMID   38254764.
  7. ↑ "Vinblastine sulfate- vinblastine sulfate injection". DailyMed. 31 December 2019. Retrieved 15 April 2020.
  8. ↑ "Vinblastine". Chemocare. Retrieved 12 November 2021.
  9. ↑ van Der Heijden R, Jacobs DI, Snoeijer W, Hallard D, Verpoorte R (March 2004). "The Catharanthus alkaloids: pharmacognosy and biotechnology". Current Medicinal Chemistry. 11 (5): 607–628. doi:10.2174/0929867043455846. PMID   15032608.
  10. ↑ Cooper R, Deakin JJ (2016). "Africa's gift to the world". Botanical Miracles: Chemistry of Plants That Changed the World. CRC Press. pp. 46–51. ISBN   9781498704304. Archived from the original on 1 August 2017.
  11. ↑ Keglevich P, Hazai L, Kalaus G, Szántay C (May 2012). "Modifications on the basic skeletons of vinblastine and vincristine". Molecules. 17 (5): 5893–5914. doi: 10.3390/molecules17055893 . PMC   6268133 . PMID   22609781.
  12. ↑ Sears JE, Boger DL (March 2015). "Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure-function properties". Accounts of Chemical Research. 48 (3): 653–662. doi:10.1021/ar500400w. PMC   4363169 . PMID   25586069.
  13. 1 2 Altmann KH (2009). "Preclinical Pharmacology and Structure-Activity Studies of Epothilones". In Mulzer JH (ed.). The Epothilones: An Outstanding Family of Anti-Tumor Agents: From Soil to the Clinic. Springer Science & Business Media. pp. 157–220. ISBN   9783211782071. Archived from the original on 11 September 2017.
  14. ↑ Starling D (January 1976). "Two ultrastructurally distinct tubulin paracrystals induced in sea-urchin eggs by vinblastine sulphate" (PDF). Journal of Cell Science. 20 (1): 79–89. doi:10.1242/jcs.20.1.79. PMID   942954. Archived (PDF) from the original on 13 January 2014.
  15. ↑ Gobbi PG, Broglia C, Merli F, Dell'Olio M, Stelitano C, Iannitto E, et al. (December 2003). "Vinblastine, bleomycin, and methotrexate chemotherapy plus irradiation for patients with early-stage, favorable Hodgkin lymphoma: the experience of the Gruppo Italiano Studio Linfomi". Cancer. 98 (11): 2393–2401. doi:10.1002/cncr.11807. hdl: 11380/4847 . PMID   14635074. S2CID   21376280.
  16. ↑ Jordan MA, Wilson L (April 2004). "Microtubules as a target for anticancer drugs". Nature Reviews. Cancer. 4 (4): 253–265. doi:10.1038/nrc1317. PMID   15057285. S2CID   10228718.
  17. ↑ Yang H, Ganguly A, Cabral F (October 2010). "Inhibition of cell migration and cell division correlates with distinct effects of microtubule inhibiting drugs". The Journal of Biological Chemistry. 285 (42): 32242–32250. doi: 10.1074/jbc.M110.160820 . PMC   2952225 . PMID   20696757.
  18. ↑ Salerni BL, Bates DJ, Albershardt TC, Lowrey CH, Eastman A (April 2010). "Vinblastine induces acute, cell cycle phase-independent apoptosis in some leukemias and lymphomas and can induce acute apoptosis in others when Mcl-1 is suppressed". Molecular Cancer Therapeutics. 9 (4): 791–802. doi:10.1158/1535-7163.MCT-10-0028. PMC   2852489 . PMID   20371726.
  19. ↑ Schinkel AH (April 1999). "P-Glycoprotein, a gatekeeper in the blood-brain barrier". Adv Drug Deliv Rev. 36 (2–3): 179–194. doi:10.1016/s0169-409x(98)00085-4. PMID   10837715.
  20. ↑ Tsuji A (October 1998). "P-glycoprotein-mediated efflux transport of anticancer drugs at the blood-brain barrier". Ther Drug Monit. 20 (5): 588–90. doi:10.1097/00007691-199810000-00024. PMID   9780140.
  21. ↑ Zhu J, Wang M, Wen W, Yu R (January 2015). "Biosynthesis and regulation of terpenoid indole alkaloids in Catharanthus roseus". Pharmacognosy Reviews. 9 (17): 24–28. doi: 10.4103/0973-7847.156323 . PMC   4441158 . PMID   26009689.
  22. ↑ Kuehne ME, Matson PA, Bornmann WG (1991). "Enantioselective Syntheses of Vinblastine, Leurosidine, Vincovaline, and 20'-epi-Vincovaline". Journal of Organic Chemistry. 56 (2): 513–528. doi:10.1021/jo00002a008.
  23. ↑ Yokoshima S, Tokuyama H, Fukuyama T (2009). "Total Synthesis of (+)-Vinblastine: Control of the Stereochemistry at C18′". The Chemical Record. 10 (2): 101–118. doi:10.1002/tcr.200900025. PMID   20394103.
  24. ↑ Verma A, Laakso I, Seppänen-Laakso T, Huhtikangas A, Riekkola ML (July 2007). "A simplified procedure for indole alkaloid extraction from Catharanthus roseus combined with a semi-synthetic production process for vinblastine". Molecules. 12 (7): 1307–1315. doi: 10.3390/12071307 . PMC   6149338 . PMID   17909486.
  25. ↑ Noble RL, Beer CT, Cutts JH (December 1958). "Role of chance observations in chemotherapy: Vinca rosea". Annals of the New York Academy of Sciences. 76 (3): 882–894. Bibcode:1958NYASA..76..882N. doi:10.1111/j.1749-6632.1958.tb54906.x. PMID   13627916. S2CID   34879726.
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